Spermicidal composition



but less than ten carbon atoms.

SPECIDAL COMPOSITION Victor R. Berliner, North Branch, William C. Mende,

Neshanik, and Heron 0. Singher, Plainfield, N. 5., assignors to OrthoPharmaceutical Corporation, a corporation of New Jersey No Drawing.Application September 27, 1952, Serial No. 311,954

6 Claims. (Cl. 167-58) This invention relates to novel compositions ofmatter and more particularly to novel compositions which are intendedfor topical use. In its more specific aspect the invention is directedto novel compositions of matter useful chiefly for application to themucous surfaces of the vaginal cavity where they act as spermicidalmedia.

A number of different spermicidal compositions have been proposedincluding those disclosed in U. S. Patent No. 2,330,846. This patentdiscloses spermicidal compositions wherein an aqueous vehicle isassociated with an unsaturated higher fatty acid of ten or more carbonatoms and a surface tension depressant, the unsaturated fatty acid beingsuspended in the vehicle in the form of finely dispersed particles.

While spermicidal compositions disclosed in the said patent have foundacceptance in the art, it has now been discovered that novel and highlyspermicidal compositions having markedly high spermicidal power may beprovided which include, as ingredients in the composition, an aliphaticorganic monoor dibasic acid, a surface tension depressant, and an acidbuffer system.

Aliphatic acids suitable for use in the formulation are monoand dibasicaliphatic acids having at least three The acids may be straight orbranch chain acids. Acids such as propionic, butyric, isobutyric,capryllic, succinic and glutamic are particularly suitable; howeversuccinic acid is the preferred acid.

The surface tension depressant employed in the formulation may bedescribed as water-soluble alkylphenoxyethanols having the followinggeneral formula: I

in which in the preferred form R is an alkyl radical having at leastseven but not more than nine carbon atoms and in which x is at leastseven but not greater than eleven. A mixture of water-solublealkylphenoxyethanols may be used. In a specific preferred practice x hasan average value of from 9.25 to 10.25, the average molecular weight ofthe water-soluble alkylphenoxyethanols is 595 to 639, and R is adiisobutyl radical having the following formula:

H; CH3 CH3CH2-C H3 B3 In the preferred specific embodiment of theinvention, 2: is approximately 9.75 and R is a tertiary octyl radical.The acid buffer system may be prepared with an aliphatic monoor dibasicacid having at least two but less than ten carbon atoms. The acid may bea straight or branch chain acid. Particularly suitable acids having useas butters include succinic, acetic, tartaric and citric acids.

A higher unsaturated fatty acid having at least ten carbon atoms mayalso be included in the formulation and has the effect of increasing thespermicidal power. Suitable 2,752,284 Patented June 26, 1956 higherunsaturated fatty acids include ricinoleic, oleic and linoleic.Ricinoleic acid is preferred. The surfacetension dispersant in theformulation enables a fine division of theunsaturated fatty acid to beobtained and this contributes substantially to the spermicidal power.

'The vehicle employed in the formulation is preferably an aqueousvehicle and cellulose derivatives are preferred as gel-formingingredients, although vegetable gums and materials such as syntheticgums may be used to produce satisfactory vehicles. A thickened masscomprising water and a vegetable gum such as tragacanth or acacia, acombination of these two vegetable gums, or other vegetable gums whichare stable at a pH within the range of from 4.0 to 8.5 may also be usedas vehicles. Cellulose derivatives such as cellulose ethers, specificexamples of which are methyl cellulose, ethyl cellulose, andcarboxymethyl cellulose, are stable at a pH within the range of from 4.0to 8.5 and form excellent aqueous vehicles when mixed with water.

Combinations of one or more cellulose derivatives or combinations of acellulose derivative and a vegetable gum may also be used in the aqueousvehicle.

In the practice of this invention there may be employed a vehicle, suchas those described above, in association with one or more aliphaticmonoand dibasic acids, one or more alkylphenoxyethanols and one or moreunsaturated fatty acids. The amount of aliphatic acid,alkylphenoxyethanol and fatty acid present in the aqueous vehicle issmall, and it is preferable that the ratio of the quantity by weightrespectively of the aliphatic acid, fatty acid and alkylphenoxyethanolto the vehicle be no greater than about 5 to and 1,0 to 100,respectively. Also present may be one or more antiseptic agents such asboric acid, oxyquinoline sulfate, phenols, cresols, thymols, chlorinatedthymols; an antimolding agent such as propyl para-hydroxy benzoate; ahygroscopic agent such as glycerine; and other substances such asperfumes and the like.

' The invention accordingly comprises compositions possessingthecharacteristics, properties and relation of constituents which will beexemplified in the compositions hereinafter described. For a betterunderstanding of the invention reference should be had to the followingexamples which are given as specific illustrations. It should beunderstood, however, that the invention is not to be limited to thespecific details set forth in the examples but that the scope of theinvention will be indicated in the claims.

The spermicidal compositions of the following examples are preparedaccording to the following general procedure in which two initialsolutions are mixed to make the formulation, all the parts being givenby weight.

The formulation of any of the following examples may be prepared asfollows:

To prepare solution A, dissolve the para-hydroxybenzoic acid in abouttwo-thirds of the hot deionized water, cool to about F. and, whilestirring well, add the gel-forming ingredient and glycerine or propyleneglycol.

To prepare solution B, add the surface tension depressant to a solutionof the higher unsaturated fatty acid in the remaining deionized waterand then add the aliphatic monoor dibasic acid; finally, add sufficientsodium hydroxide to adjust to the desired pH. The formulation resultsfrom adding solution B to solution A in a slow stream with goodstirring; stirring is then continued for at least one hour.

Para-hydroxy-benzoic acid methyl ester 0.20

A mixture of para-diisobutylphenoxypolyethanols having the generalformula:

(3H3 CH: CH3-CCHz-& (OOHr-"CHQ)ZOH CH3 H3 7 in which 2: has anapproximate value of 9.75.. 1.00 Succinic acid 5.00 Ricinoleic acid 2.70

EXAMPLE II Deionized water 89.30 Sodium carboxymethylcellulose 3.50Propylene glycol 5.00 Para-hydroxy-benzoic acid methyl ester 0.20 Amixture of para-diisobutylphenoxypolyethanols having the generalformula:

CH: CH: cm-h-om i: ocm-om .on

(EH: CH2. in which x has an approximate value of 9.75 1.00 Succinic acid-4 1.00

EXAMPLE III Deionized water 89.06 Hydroxyethyl cellulose 3.50 Propyleneglycol 5.00 Para-hydroxy-benzoic acid methyl ester 0.20 A mixture ofpara-diisobutylphenoxypolyethanols having the general formula: (3H3 CH3GHS-CGHR (E (OCHZ'HCHQ):OH

in which x has an approximate value of 9.75 1.00 Adipic acid 1.24

EXAMPLE IV Deionized water 88.94 Methyl cellulose 3.50 Propylene glycol5.00 Para-hydroxy-benzoic acid methyl ester 0.20 A mixture ofpara-diisobutylphenoxypolyethanols having the general formula: $113 CH3om-cqnn-aL-O(on, om .-on

(1H1 OH: in which x has an approximate value of 9.75 1.00 Pimelic acid1.36

EXAMPLE V Deionized water 88.13 Sodium alginate 3.50 Propylene glycol5.00 Para-hydroxy-benzoic acid methyl ester 0.20 A mixture ofpara-diisobutylphenoxypolyethanols having the general formula: ()Ha (3H3curh-oH2- :C oorn-o11z).o11

CH3 OH;

in which as has an approximate value of 9.75 1.00 SucCinic acid 1.00Oleic acid 1.17

EXAMPLE VI Deionized water 87.89 Gum tragacanth 3.50 Propylene glycol5.00 Para-hydroxy-benzoic acid methyl ester 0.20

A mixture of para-diisobutylphenoxypolyethanols having the generalformula:

spermicidal compositions were tested to determine their spermicidalpower according to the following procedure: One gram of a spermicidalcomposition represented by Examples I to VII, inclusive, was placed in atest tube containing 99 grams of a physiological saline solutionbuttered at a pH of from 3.9 to 4.1. The saline solution contained 9.0grams of sodium chloride per liter of water, and the butter used in thesaline was potassium acid phthalate and sodium phosphate. The butteredsaline alone is not spermicidal and does not have the property ofimmotilizing sperm. The test tube was shaken vigorously until the jellywas uniformly distributed in the saline solution. One cc. of the jellyin saline solution was added to a second test tube containing 0.2 cc. offresh human semen; the contents of the second tube were quickly mixedand examined microscopically to determine the activity of thespermatozoa. The time required for the mixing of the contents of thesecond test tube, the placing of a sample on a suitable slide, and itssubsequent microscopic examination required a minimum of 20 seconds;therefore, results of tests listed as 20 seconds indicate that whenfirst viewed under the microscope, the spermatozoa were immotile. Ininstances where the spermatozoa still showed motility when firstexamined under the microscope, the exact time when they becamecompletely immotilized was found by constant observation of the testsample on the microscopic slide and this time is taken as killing timefor immotile sperm are incapable of fertilizing an ovum or of regainingmotility.

Three series of tests were made at intervals of a few days to determinethe spermicidal activity of the formulations of the examples. Eachformulation was tested three times. Each series of tests was made on asample of human semen resulting from the pooling of individual specimensfrom three donors. The semen specimens were collected, pooled and usedwithin a few hours to insure that the spermatozoa had full motility atthe time the tests were made. In all cases spermatozoa were com pletelyimmotile in less than 20 seconds.

In order that the spermicidal power of the formulation be of a highorder it is necessary that the aliphatic monoor dibasic acid be presentin a concentration suflicient that at least 20 millimols per liter ofundissociated acid be present in the formulation. The concentration ofacid required in order that this minimum amount of undissociated acid bepresent in the formulation varies with the acid used; the requiredminimum concentration of succinic acid is 0.085 molar. The greater themolecular weight of the acid, the less undissociated acid is required,but a minimum of 20 millimols of undissociatcd acid in the formulationis necessary in order that the formulation have a killing time of 20seconds when tested according to the procedure given above. Thespermicidal time of the formulations of the above examples is a functionof the amount of residual undissociated acid present after theformulation and sperm have been mixed and a formulation having at least20 millimols of undissociated acid will furnish suficient undissociatedacid on mixing with sperm to kill sperm in a maximum of 20 seconds whentested by the procedure given above. The formulation may be bufieredover a wide pH range but this range is limited by the necessity to avoidirritation of the vaginal mucosa. Formulations having a pH within therange of from 4 to 8.5, and a concentration of buffer below the criticalvalue given below, have a sufiiciently low incidence of irritation to besatisfactory for use as contraceptive formulations. At pH values low inthe non-irritation range, a lesser amount of undissociated acid isrequired than at pH values high in the acid range in order that thespermicidal time be less than 20 seconds according to the above tests.

The amount of undissociated acid required to be present when theformulation is mixed with sperm in order that the spermicidal time beless than 20 seconds is greater when the molecular weight of thealiphatic acid is lower than when the molecular weight of the acid isclose to the upper limit. In a formulation in which the aliphatic acidhas three carbon atoms, there must be present at least 35 millimols ofundissociated acid in a formulation buffered at pH 4.5; however, whenthe aliphatic acid has nine carbon atoms it is only necessary that therebe 20 millimols of undissociated acid present in a formulation bufferedat pH 4.5.

It is necessary that the buffering capacity of the formulation beequivalent to the buffering capacity of any of the acids'listed above assuitable for use in the preparation of the acid buffer system when theacid is present in a concentration of less than 0.775 molar but greaterthan 0.01 molar. The acid of the buffer system must be sufiicientlywater-soluble to be present in the solution in the concentrationrequired to give a buffering capacity within the above range. If thebuffering capacity is less than 0.01 molar, the undissociated acidpresent in the formulation will not be within the required range. If thebuffering capacity is greater than 0.775 molar, the concentration ofacid will be so high that undesirable incidences of irritation ofvaginal mucosa will result. Bufiering capacity may be defined as theconcentration of the buifer present multiplied by its bulfer index.Buffer index may be defined as the amount of alkali necessary to shiftthe pH one pH unit within a given pH range.

The results in Table I represent killing time in seconds, determinedaccording to the above procedure, for a series of formulationscorresponding to the formulation of Example I except that the amount ofsuccinic acid was varied to give a series of jels with increasing acidconcentration and buifering capacity, expressed in mols per liter. Allformulations were adjusted to a pH of 4.5. The buffer index of succinicacid is 5.84.

Table l Buffering Acid Concentration Capacity Killing Time 61. less than20.

in these formulations. Total acid concentration of each formulation isexpressed in moles per liter. formulations were adjusted to a pH of 4.5.

Table II Acid Concentration Killing time Succinic 0. 0095 600. Sebacic.0.009 40. Lactic i 0.001 800. Pimelic. 0. 002 35. succinic 0.010 lessthan 20.

Table III Undissociated Acid Killing Time less than 20. 35.

The results in Table IV represent killing time in seconds, determinedaccording to the above procedure except that in making the tests equalvolumes of the formulation and semen were mixed, for a series offormulations corresponding to the formulation of Example I except thatin part of the formulations tested succinic acid was replaced withisocaproic acid and propionic acid and the concentration ofundissociated acid was varied to give three series of gels, each withincreasing amounts of undissociated acid expressed in millimols perliter. The pH values of Table IV are for the mixture of formulation andsemen. The results show that for any particular acid the amount ofundissociated acid required so that the formulation will have a killingtime of less than 20 seconds increases as the pH increases from 4 to7.4.

Table IV Undis- Acid pH sociated Killing Time Acid 4. 5 35 less than 20.7. 2 35 210.

7. 4 42 less than 20. 4. 5 30 Do.

7. 4 40 less than 20 4. 0 23 Do.

5. 0 30 less than 20.

It will be apparent to those skilled in the art that numerousvariations, modifications, and extensions of the principles involved maybe made without departing from the spirit and scope of the invention.All such variations, modifications, and extensions are to be understoodas included within the ambit of the appended claims.

What is claimed is:

1. A spermicidal composition comprising in combination with a vehicle, awater-soluble alkylphenoxyethanol having the formula in which R is analkyl radical having at least seven but not more than nine carbon atomsand x is at least seven but not greater than eleven, an aliphatic acidselected from the class consisting of monoand dibasic aliphatic acidshaving at least three but less than ten carbon atoms in a concentrationsuch that at least 20 millimols per liter of undissociated acid arepresent in the formulation, an acid butter system, in which the acid isselected from the class consisting of monoand dibasic aliphatic acidshaving at least two but less than ten carbon atoms, that maintains thepH of the formulation within the range of from about four to about eightand one-half and a higher unsaturated fatty acid having at least tencarbon atoms.

2. A composition according to claim 1 in which the aliphatic acid issuccinic acid and the acid in the acid buffer system is succinic acid.

3. A composition according to claim 1 in which the aliphatic acid issuccinic acid and the acid in the acid bufier system is acetic acid.

4. A spermicidal composition comprising in combination with a vehicle, amixture of Water-soluble alkylphenoxyethanols having the formulanOwongonmon in which R is a diisobutyl radical, the average value of xin said mixture is 9.25 to 10.25 and the average molecular weight isapproximately 595 to 639, an aliphatic acid selected from the classconsisting of monoand dibasic aliphatic acids having at least three butless than ten carbon atoms in a concentration such that at least 29millimols per liter of nndissociated acid are present in theformulation, an acid bufier system, in which the acid is selected fromthe class consisting of monoand dibasic aliphatic acids having at leasttwo but less than ten carbon atoms, that maintains the pH of theformulation within the range of from about four to about eight andone-half and a higher unsaturated fatty acid having at least ten carbonatoms.

5. A composition according to claim 4 in which the aliphatic acid issuccinic acid and the acid in the acid bufifer system is succinic acid.

6. A composition according to claim 4 in which the aliphatic acid issuccinic acid and the acid in the acid bnfier system is acetic acid.

References Cited in the file of this patent UNITED STATES PATENTS2,436,184 Stillman Feb. 17, 1948 2,467,884 Elias Apr. 19, 1949 2,541,103Sander Feb. 13, 1951 2,556,567 Wright June 12, 1951 OTHER REFERENCESShedlovsky: The Journal of Contraception, vol. 2, Nos. 8-9, Aug-Sept.1937, pgs. 147-155.

Baker: Journal of Hygiene, vol. 31, April 1931, pgs. 189, 191, 199,210-213.

1. A SPERMICIDAL COMPOSITION COMPRISING IN COMBINATION WITH A VEHICLE, AWATER-SOLUBLE ALKYLPHENOXYETHANOL HAVING THE FORMULA